This BRP grant application describes a pioneering, integrated lightweight neuromotor prosthetic microsystem (NMP) for paralyzed humans: NMPs use neural activity as a direct output to machines that run assistive devices. To meet this goal we have assembled an interdisciplinary team that combines leaders in neuroscience (Donoghue) and engineering (Nurmikko), with support from computer science (Black) at Brown University and neurology/neurosurgery at Brown and at Massachusetts General Hospital (Hochberg);experts in NMP design, development, manufacturing and commercialization from Cybernetics, Inc. (CKI), a neurotechnology company;and experts in neural prosthesis development and human application at the Cleveland FES center/Case Western University (H. Peckham/R. Kirsch). We will develop an integrated and implantable microelectronic neurosensor system that features on-chip signal processing and wide bandwidth transcutaneous wireless transmission capabilities. The high performance microsystem incorporates cutting-edge ultralow power microelectronics and is designed to be technologically flexible and modular, to enable scaling to increasingly complex neural signal extraction and manipulation. Its components imbed adaptive processors for automated calibration and set-up which exploit neural decoding algorithms, currently being developed at Brown, to provide a stable, multipurpose output signal. The microsystem implant will be first tested in animal models (motor cortex of monkeys) to establish efficacy, biocompatibility and biostability. We will input learning acquired from ongoing and future human trial patients with the present percutaneous cabling system to establish principles of human NMP operation for adapting the implantable microsystem design, the role of learning in NMP use, and the limits of human NMP control. We will pursue the federal regulatory pathways to gain approval for the NMP microsystem while developing the assistive technology for human patients. The end goal of this BRP grant is to achieve the implantation and testing of the new microsystem chronically in a human patient. t 'The ultimate vision and guiding light for this BRP proposal is to develop the technological infrastructure to achieve a longer term goal, namely system is the restoration of semi-autonomous, closed-loop, distributed- feedback control of a limb that has lost spinal cord connection to the motor cortex.